Krill oil is a unique marine oil containing omega-3 or n-3 fatty acids (FAs), wherein the bioactive eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are present (i.e., comprising up to 35%w/w, of the FA profile) mainly in phospholipids or PLs (up to 95%w/w), and containing up to 60% PLs and up to 45% triglycerides in the oil.1 In contrast, current sources of n3-FAs in commercial parenteral or injectable lipid emulsions consist of approximately 30 to 60%w/w concentration, but are nearly entirely contained in fish oil triglycerides (TG). Of note, the European Pharmacopeia (Pharm Eur) has two official monographs for n3-FAs derived from fish oil triglycerides. The first monograph was adopted in 1999 and includes the following title, monograph number and specifications:    1. Omega-3 Acid Triglycerides, Pharm Eur Monograph 1352 (Omega-3 acidorum triglyceride)            Content:                    Sum of the contents of the omega-3 acids EPA and DHA, expressed as triglycerides: minimum 45.0 percent; total omega-3 acids, expressed as triglycerides: minimum 60.0 percent.In 2005, a second Pharm Eur monograph was adopted and includes the following title, monograph number and specifications:                            2. Fish Oil, Rich in Omega-3 Acids, Pharm Eur Monograph 1912 (Piscis oleum omega-3 acidis abundans)            Content:                    EPA, expressed as triglycerides: minimum 13.0 percent, DHA, expressed as triglycerides: minimum: 9.0 percent, total omega-3 acids, expressed as triglycerides: minimum 28.0 percent.                        
Of the two monographs, only Pharm Eur Monograph 1352 is specifically indicated for parenteral use.2 However, depending upon the manufacturer, two commercially available parenteral emulsions employ the pharmacopeial standards of either Monograph 1352 or 1912, i.e., one brand of fish oil-containing injectable emulsion contains approximately one-half the concentration of the bioactive omega-3 fatty acids, EPA and DHA vs. another brand of fish oil-containing emulsion, and hence they are not bioequivalent.3 Ideally, it may be beneficial to employ the specifications of Pharm Eur Monograph 1352, a greatly purified fish oil triglyceride source of n3-FAs, especially when administered by the intravenous route of administration.
Omega-3 fatty acids are classified as highly polyunsaturated fatty acids (PUFA), containing multiple double bonds that are extremely susceptible to oxidative degradation. Unsaturated fatty acids have specific nomenclature involving 3 general terms: 1) number of carbons; 2) number of double bonds; and, 3) the carbon containing the first double bond. There are 3 main families of unsaturated fatty acids important in human metabolism and they include the omega-3's (e.g., EPA containing 20 carbons, 5 double bonds beginning on the 3rd carbon from the methyl end of the hydrocarbon chain, denoted as 20:5n3); the omega-6's (e.g., arachidonic acid, or AA, containing 20 carbons, 4 double bonds beginning on the 6th carbon, denoted as 20:4n6); and finally, the omega-9's (e.g., oleic acid containing 18 carbons, 1 double bond beginning on the 9th carbon, denoted as 18:1n9). They are classified as highly polyunsaturated, polyunsaturated, and monounsaturated fatty acids, respectively. Oxidation of highly PUFAs, such as EPA (20:5n3) and DHA (22:6n3), not only degrades their important clinical bioactivities (such as therapeutic decreases in: inflammation, oxidative stress, immunosuppression and ischemia), but also produces volatile degradation products known as reactive oxygen species, that may have clinically relevant and harmful side effects to vital organs (e.g., heart, brain, lungs, liver and kidneys), especially in critically ill patients during acute metabolic stress (i.e., the systemic inflammatory response syndrome). Therefore, minimizing the oxidation of vegetable- or marine-based polyunsaturated fatty acids in injectable lipid emulsions is desirable. This can be achieved based on the location of the polyunsaturated fatty acid on the glyceride backbone, with position-2 being most preferable in this regard (as well as with respect to bioavailability). Alternatively, antioxidants, such as alpha tocopherol, are either naturally present in small amounts (e.g., alpha-tocopherol in soybean oil, ˜20 mg/L) or are added to the lipid injectable emulsion formulation in amounts approximating 200 mg/L. Alpha-tocopherol is an example of a parenteral antioxidant that protects these bioactive fatty acids from chemical breakdown and subsequent potential clinical harm, and it is recognized as a suitable parenteral pharmaceutical adjuvant by both the European and the United States Pharmacopeias (USP). On the other hand, in addition to its high PL contents, krill oil possesses another unique attribute, in that it contains the naturally occurring antioxidant, astaxanthin, but in amounts 10× to 100× higher than the antioxidants naturally found in commonly used polyunsaturated triglyceride oil-in-water parenteral emulsions.1 Astaxanthin is not approved for use in humans as a parenteral surfactant.
Despite this benefit, the uniquely high PL content of krill oil (e.g., in its current composition1) may render it unsuitable as a major source of n-3 FAs in lipid injectable emulsions. Current parenteral dispersions contain egg phospholipids as a surfactant to stabilize various triglyceride oil-in-water (o/w) emulsions. Like egg phospholipids, phosphatidyl choline is a major phosphatide in krill oil phospholipids.4 The proportion of phospholipids to triglycerides (PL:TG ratio) in injectable lipid emulsion formulations should be no greater than 0.06. For example, a standard 20% soybean oil-in-water injectable lipid emulsion contains 12 g/L of PL and 200 g/L of triglycerides. Higher PL:TG ratios (i.e., 0.12, e.g., 10% oil-in-water emulsions with 12 g/L of egg PL) have been shown to interfere with lipoprotein lipase and impair plasma clearance of infused triglycerides (i.e., hypertriglyceridemia) in acutely ill infants, and in adults at high infusion rates.5 Therefore, using krill oil in its present form as the principal lipid source in injectable emulsions does not seem to be clinically acceptable.
Another high concentration parenteral phospholipid-based injectable emulsion (92.5% phosphatidyl choline/7.5% triglyceride) has been given in an attempt to neutralize the clinical sequelae from bacterial endotoxin.6 Although some benefits were observed, the primary study endpoint, a non-parametric “clinical scoring system” based on various symptoms (chills, headaches, myalgias, nausea and headaches), was applied and analyzed by parametric statistical methods (i.e., a 2-tailed t-test). However, this significant design flaw negated the purported benefits of the study. A follow-up randomized clinical trial involving 235 medical centers worldwide showed no significant benefit on 28-day all-cause mortality, nor was there a reduction in the onset of new organ failure.7 Moreover, the high-dose arm of the study had to be stopped due to an increase in life-threatening adverse events. It is possible, as with effective parenteral surfactants, that a mixture of phosphatides is more efficacious as a pharmaceutical aid, and that a similar composition may be needed for clinical safety and efficacy in this patient population.